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Objective: High disease activity status (HDAS) in patients with systemic lupus erythematosus (SLE) is associated with adverse long-term outcomes. We examined the frequency of lupus low disease activity state (LLDAS) and remission (REM) attainment in HDAS patients and whether their attainment was associated with improved patient outcomes., Methods: Demographic, clinical and outcomes data, collected prospectively from a multinational cohort between 2013 and 2020, were analysed. Disease activity was assessed using SLEDAI-2K. HDAS was defined as SLEDAI-2K ≥ 10. Patients' first visit with SLEDAI-2K ≥ 10 was assigned as baseline. Survival analyses were performed to examine the associations between cumulative and sustained LLDAS and REM attainment in HDAS patients and subsequent organ damage accrual and flare., Results: 1,029 HDAS patients with a median study duration of 2.7 years [IQR: 1.0, 4.8] were studied. LLDAS and REM were attained at least once by 71% (LLDAS-ever, n = 726) and 41% (REM-ever, n = 418) of patients. Approximately one-fifth of patients attained ≥50% cumulative time in LLDAS or REM. 37% (n = 385) of patients attained ≥3months of sustained LLDAS, with progressively lower proportions of patients attaining longer periods of sustained LLDAS. Lower proportions of patients attained sustained REM. Attainment of cumulative and sustained LLDAS or REM provided significant protection against damage accrual and flare in HDAS patients. Sustained periods of LLDAS and REM were difficult to achieve and therefore a more stringent target, but provided the most protection against damage accrual or flare., Conclusion: LLDAS and REM were achievable targets in HDAS patients, and provided significant protection against adverse outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The first inhabitants of Australia and the traditional owners of Australian lands are the Aboriginal and Torres Strait Islander peoples. Aboriginal and Torres Strait Islander peoples are two to four times more likely to have systemic lupus erythematosus (SLE) than the general Australian population. Phenotypically, SLE appears distinctive in Aboriginal and Torres Strait Islander peoples and its severity is substantially increased, with mortality rates up to six times higher than in the general Australian population with SLE. In particular, Aboriginal and Torres Strait Islander peoples with SLE have increased prevalence of lupus nephritis and increased rates of progression to end-stage kidney disease. The reasons for the increased prevalence and severity of SLE in this population are unclear, but socioeconomic, environmental, and biological factors are all likely to be implicated, although there are no published studies investigating these factors in Aboriginal and Torres Strait Islander peoples with SLE specifically, indicating an important knowledge gap. In this Review, we summarise the data on the incidence, prevalence, and clinical and biological findings relating to SLE in Aboriginal and Torres Strait Islander peoples and explore potential factors contributing to its increased prevalence and severity in this population. Importantly, we identify health disparities and deficiencies in health-care provision that limit optimal care and outcomes for many Aboriginal and Torres Strait Islander peoples with SLE and highlight potentially addressable goals to improve outcomes., Competing Interests: Declaration of interests FBV has received support from Janssen-Cilag and CSL for projects described in the scope of this Review and from Pfizer, Lupus Research Alliance, and SomaLogic for conference or meeting sponsorship. SK has received support from Pfizer for conference sponsorship. AYH has received support from Arthritis Australia, Perpetual IMPACT fund, AstraZeneca, Bristol Myers Squibb, Merck Serono, GSK, Eli Lilly, Union Chimique Belge (UCB), and Janssen. AYH also received honoraria from Novartis, Janssen, and Recordati. EFM has received grant or research support from AbbVie, Amgen, Biogen, AstraZeneca, Bristol Myers Squibb, Janssen, Eli Lilly, EMD Serono, Genentech, GSK, and UCB. EFM received consultant fees from EMD Serono, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genentech, GSK, Janssen, Novartis, AbbVie, Galapagos, and IgM; honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, EMD Serono, and Gilead; and travel support from AstraZeneca. EFM is Board Director of Rare Voices Australia, a not-for-profit organisation. MR received research grants for SLE clinical trials from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, GSK, Janssen, Lilly, Novartis, Pfizer, Servier, and UCB. MR received consulting fees from AbbVie, Boehringer Ingelheim, Janssen Global Services, Novartis, and Pfizer., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: The lupus low disease activity state (LLDAS) allows for certain clinical and/or serological activity of SLE, provided overall disease activity does not exceed predefined cut-offs. This study aimed to evaluate the outcomes of patients who achieved LLDAS with clinical activity, serological activity only or neither clinical nor serological activity., Methods: Patients with SLE enrolled in a prospective multinational cohort from March 2013 to December 2020 who were in LLDAS at least once were included. Visits that fulfilled both LLDAS and Definition of Remission in SLE (DORIS) criteria were excluded., Results: 2099 patients were included, with median follow-up of 3.5 (IQR 1.3-5.8) years. At 6150 visits, patients were in LLDAS but not DORIS criteria; of these 1280 (20.8%) had some clinical activity, 3102 (50.4%) visits had serological activity only and 1768 (28.8%) visits had neither clinical nor serological activity. Multivariable regression analysis showed that compared with non-LLDAS, all three subsets of LLDAS had a protective association with flares in the ensuing 6 months and damage accrual in the ensuing 36 months. LLDAS with no clinical or serological activity had a significantly stronger protective association with severe flares in the ensuing 6 months compared with LLDAS with clinical activity (HR 0.47, 95% CI (0.27 to 0.82), p=0.007)., Conclusions: LLDAS without any clinical activity accounted for almost 80% of LLDAS visits. This study confirms that all subsets of LLDAS are associated with reduced flare and damage accrual. However, LLDAS without any clinical or serological activity has the strongest protective association with severe flares., Competing Interests: Competing interests: SO'N received consulting fees from AstraZeneca, Biogen, Boehringer Ingelheim; lecture/speaker fees from AstraZeneca, Biogen, Boehringer Ingelheim, Pfizer and GSK and research grants from Aurania, Biogen, Idorsia, Novartis. ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol-Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB and have royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol-Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB. SS received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics. YK received payment/Honoria from Asahi Kasei, Astellas, AstraZeneca, Chugai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Pfizer Japan and Sanofi. MH received speaker’s fee from AbbVie Japan, Ayumi, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly Japan, GlaxoSmithKline, Kissei Pharmaceutical, Pfizer Japan, Takeda and Teijin; consultant fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Kissei Pharmaceutical and Teijin and research grants from AbbVie Japan GK, Asahi Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo. Eisai, KisseiPharmaceutical, Mitsubishi Tanabe, Nippon Kayaku, Sekisui Medical, Shionogi, Taisho, Takeda and Teijin. TT received grants from Astellas, Asahi Kasei, Chugai, Mitsubishi Tanabe, and consulting fees from Astellas, Chugai. KN received Advisory Board participation fees from AbbVie. YT has received research grants from Eli Lilly, AstraZeneca, AbbVie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer and Taiho. AH received research grants from AstraZeneca, and consulting fees from EUSA Pharma (UK), and Speaker/Honoraria from Limbic, Novartis, Moose Republic, AbbVie, Eli Lilly. RK-R received research grants from Novartis and GlaxoSmithKline. EM received research grants and/or consulting fees from AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Genentech, GlaxoSmithKline, Genentech, Janssen, Novartis, Servier, EMD Serono, Takeda and UCB. MN received research grants and honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Janssen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission., Methods: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941., Findings: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS., Interpretation: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission., Funding: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB., Competing Interests: Declaration of interests RK-R received grants from GSK and Novartis. SVN received consulting fees from Biogen, Boehringer Ingelheim, Astra Zeneca, Idorsia; payment for lectures from AstraZeneca, Boehringer Ingelheim, GSK, and Roche; participation in advisory board for Biogen; and leadership of societies, unpaid (CEO of Rheumatology Educational Trust Foundation, and Head of the SLE Special Interest Group at the Philippine Rheumatology Association). ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB, and has royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB. SS received consulting fees from Pfizer, AstraZeneca, and ZP Therapeutics. YK received payment or honoraria from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MH received institutional research grants from GSK and Novartis; and honoraria for lectures from AstraZeneca and Astellas Pharma. ZZ received payment or honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Novartis, Pfizer, Roche, Sanofi, Janssen, and UCB; and participation in advisory board for Beigene. JK received speaker fees from GSK and Asahi Kasei. TT received grants from Astellas, Asahi Kasei, Chugai, and Mitsubishi Tanabe, and consulting fees from Astellas and Chugai. FG is Director of the Board of the Australian Rheumatology Association. KN received Advisory Board participation fees from AbbVie. YT received research grants from Boehringer Ingelheim, Taisho, and Chugai; and speaker fees or honoraria from AbbVie, Eisai, Chugai, Eli Lilly, Boehringer Ingelheim, GSK, Taisho, AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, and Astellas. AH received a research grant from AstraZeneca; consulting fees from EUSA Pharma (UK); and speaker fees or honoraria from Limbic, Novartis, Moose Republic, AbbVie, and Eli Lilly. MN received an Investigator Grant from the National Health and Medical Research Council of Australia (NHMRC GNT1176538); research grants from Janssen and Boehringer Ingelheim; consulting fees from AstraZeneca and GSK; honoraria for presentations from AstraZeneca, GSK, and Boehringer Ingelheim; and support for conference attendance from Boehringer Ingelheim. EFM received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genetech, Janssen, Novartis, Servier, and EMD Serono. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE)., Methods: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare., Results: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up., Conclusion: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941)., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE)., Methods: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred., Results: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day., Conclusions: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients., Competing Interests: Competing interests: YK received honoraria from Asahi Kasei Pharma, Astellas Pharma, AstraZeneca K.K., Chugai Pharmaceutical, GlaxoSmithKline KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma Corporation, Pfizer Japan, Sanofi KK. EI received honoraria from Bristol-Myers Squibb KK, Eisai and consulting fees from Nippontect Systems. MH received honoraria from AbbVie GK, Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer Japan, Takeda Pharmaceutical, Teijin Pharma, consulting fees from AbbVie GK, Bristol-Myers Squibb K.K., Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Teijin Pharma, grant/research support from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Sekisui Medical, Shionogi, Taisho Pharmaceutical, Takeda Pharmaceutical, Teijin Pharma. AH received honoraria from UCB, Janssen, Sandoz, Eli Lilly, consulting fees from AbbVie, GSK and grant/research support from AstraZeneca, GSK, Bristol Myers Squibb, Janssen, Merck Serono. CSL received honoraria from AstraZeneca UK and consulting fee from AstraZeneca Pharmaceuticals LP. ZL received honoraria from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma and consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma. SS received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics and grant/research support from Pfizer, AstraZeneca, ZP Therapeutics. SVN received consulting fees from Biogen, Boehringer Ingelheim, AstraZeneca, grant/research support from Jannsen, Novartis, Pfizer, GSK and support for attending meetings from Biogen. SOon received royalty from Venetoclax. KN is on the advisory board for AbbVie. TT received honoraria from AbbVie GK, Chugai Pharmaceutical, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma, consulting fees from AbbVie GK, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma and grant/research support from AbbVie GK, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma. YT received honoraria from AbbVie GK, Asahi Kasei Pharma, AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Eli Lilly Japan K.K., Gilead Sciences, GlaxoSmithKline K.K., Nippon Boehringer Ingelheim, Pfizer Japan, Taiho Pharmaceutical, Taisho Pharmaceutical and grant/research support from Asahi Kasei Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical. MN received honoraria from Actelion, GSK, Janssen, Pfizer, UCB, consulting fees from Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB and grant/research support from Actelion, AstraZeneca, Bristol Myers Squibb, GSK, Janssen, UCB. EFM received honoraria from AstraZeneca, EMD Serono, Gilead, consulting fees from AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Novartis and grant/research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, UCB. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Introduction: We aim to report on the feasibility of establishment of the first paediatric cohort as part of the longitudinal database of the Australian Lupus Registry and Biobank (ALRB) and to describe the enrolment data with a focus on clinical characteristics, serological data, treatment strategies and patient/parent-reported outcome measures., Methods: All patients under the age of 18 years with a diagnosis of systemic lupus erythematosus (SLE) attending the paediatric rheumatology service of a single, tertiary hospital were identified. Patients were enrolled in the ALRB if they met ≥4/11 of the American College of Rheumatology (ACR) 1997 SLE classification criteria or the Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria. Enrolment data including demographics, clinical characteristics, serological profiles, disease activity and damage assessments were recorded. Peds-QL Rheumatology and General Modules were used to assess patient and parent-reported outcomes., Results: Twenty-seven patients were eligible for inclusion, with 26 patients (96%) consenting for enrolment. Twenty-five patients (92%) consented for biobanking. Twenty patients (77%) were female. The median age at enrolment was 16 years (interquartile range (IQR) 13.7, 17.4). The median disease duration from diagnosis was 3.2 years (IQR 1.4, 5.3). Sixteen patients (62%) had synovitis, 16 (62%) had cutaneous involvement, 4 (15%) had serositis, 17 (65%) had haematological involvement and 7 (27%) had renal involvement at enrolment. Nineteen patients (73%) were prescribed at least two disease-modifying anti-rheumatic medications (DMARDs). Hydroxychloroquine ( n = 22, 85%) and mycophenolate mofetil ( n = 9, 35%) were the most commonly prescribed DMARDs. The median SLEDAI-2K score was 2 (IQR 2, 4). Six patients (23%) had active disease (SLEDAI-2K ≥6) at enrolment. Three patients (11.5%) had reported damage using the SLICC/ACR Damage Index. Twenty-three children (88%) and eighteen parents (69%) completed the Paediatric Quality of Life Inventory. Quality of life scores reported across domains of physical, emotional, social and school functioning at enrolment were comparable to previously studied paediatric cohorts with SLE and other chronic diseases., Conclusion: We have established our centre as the first paediatric participating site of the ALRB, providing contemporary data on the clinical characteristics, serological profile and health-related quality of life outcomes of Australian children with SLE. Paediatric involvement with this national registry will provide a unique perspective for future clinical and scientific research. Collection of Australian-specific paediatric longitudinal data will also enable a broader understanding of SLE within a multicultural Australian population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data., Methods: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes., Results: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual., Conclusions: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus., (© 2024. The Author(s).)

Objective: Irreversible organ damage is common in patients with systemic lupus erythematosus (SLE). Despite evidence of increased prevalence and severity of SLE in Asia Pacific, organ damage is less well studied in this region. This systematic review aims to identify predictors of organ damage in SLE in the Asia Pacific region., Methods: We searched Medline, PubMed, Embase, and Web of Science for observational studies on organ damage in adult patients with SLE in Asia Pacific from August 31, to September 5, 2022. Study selection and data extraction were completed by two independent reviewers using Covidence systematic review software. Risk of bias was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute tool. Significant results from univariable and multivariable analyses were synthesized from included studies., Results: Thirty-eight eligible studies were selected from 1999 to 2022; 22 (58%) of these reported organ damage at study enrollment and 19 (50%) reported damage accrual, as measured by the Systemic Lupus International Collaborating Clinic/American College of Rheumatology Damage Index. Factors predictive of organ damage included older age, glucocorticoid use, longer disease duration, and disease activity. Lupus nephritis was a risk factor for renal and overall damage accrual. Hydroxychloroquine was protective against overall organ damage., Conclusion: Predictors of organ damage in SLE in Asia Pacific are similar to other regions. Although glucocorticoid use is a modifiable risk factor for organ damage, the impact of immunosuppressives and biologic therapies needs further investigation. Effective strategies in early disease are needed to minimize initial organ damage as it predicts subsequent damage accrual., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Autoimmune rheumatic disease (AIRD) is a collective term, which comprises a group of multisystem inflammatory autoimmune diseases, including connective tissue disease, chronic inflammatory arthritis, sarcoidosis and systemic vasculitis. Some AIRD are prevalent in the general population, and all can cause significant morbidity and reduced quality of life, with some increasing the risk of premature mortality, such as systemic lupus erythematosus (SLE), a connective tissue disease that is more prevalent and severe in Australian Aboriginal and Torres Strait Islander Peoples with high mortality rates. To ensure that management of AIRD can be optimised for all Australians, it is important that we understand the prevalence and potential phenotypic variations of AIRD across the Australian population. However, to date there have been few described cases of AIRD other than SLE in Aboriginal and Torres Strait Islander Peoples. In this review, we summarise what is known about AIRD other than SLE in Aboriginal and Torres Strait Islander Peoples, particularly with regards to prevalence, phenotype and disease outcomes, and highlight the current gaps in knowledge., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE., (© 2024. The Author(s).)

Objective: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive., Methods: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare., Results: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009)., Conclusion: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Remission is the established therapeutic goal for patients with systemic lupus erythematosus (SLE) and is currently defined by the widely adopted Definition Of Remission In SLE (DORIS) criteria. Attainment of remission is rare in the clinical setting, thus an alternative, pragmatic treatment target of low disease activity, as defined by the Lupus Low Disease Activity State (LLDAS), provides a less stringent and more attainable treatment goal for a wider proportion of patients compared with DORIS remission. Randomized controlled trials and real-world analyses have confirmed the positive clinical benefits of achieving either DORIS remission or LLDAS. The treat-to-target (T2T) approach utilizes practical clinical targets to proactively tailor individual treatment regimens. Studies in other chronic inflammatory diseases using the T2T approach demonstrated significantly improved clinical outcomes and quality-of-life measures compared with established standard of care. However, such trials have not yet been performed in patients with SLE. Here we review the evolution of DORIS remission and LLDAS definitions and the evidence supporting the positive clinical outcomes following DORIS remission or LLDAS attainment, before discussing considerations for implementation of these outcome measures as potential T2T objectives. Adoption of DORIS remission and LLDAS treatment goals may result in favorable patient outcomes compared with established standard of care for patients with SLE., (© 2023. The Author(s).)

Background: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission., Methods: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission., Findings: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare., Interpretation: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months., Funding: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB., Competing Interests: Declaration of interests YK received honoraria from GSK, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MHa received payment for post-marketing surveillance from GSK; research grants from Novartis; and honoraria from GSK, AstraZeneca, and Astella Pharma. TT received research grants from Astellas Pharma, Asahi Kasei, Chugai, and Mitsubishi Tanabe, as well as consulting fees from Astellas Pharma and Chugai. KPKN is on the advisory board for AbbVie. SVN received consulting fees from Biogen and Boehringer Ingelheim; honoraria from Janssen, Novartis, Pfizer, and GSK; support for attending meetings from Pfizer; and is on the advisory board for Biogen. EFM received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Genentech, Janssen, Novartis, Servier, EMD, Serono, and Eli Lily. MN received research grants from Janssen; consulting fees from AstraZeneca, Boehringer Ingelheim, GSK, and Janssen; and honoraria from Janssen, Boehringer Ingelheim, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician-academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development., (© 2023. Springer Nature Limited.)

Objectives: We compared the US norm-based two-component vs. Japanese norm-based three-component summary scores of the Medical Outcomes Study Short Form-36 (SF-36) in patients with systemic lupus erythematosus (SLE)., Methods: One hundred fourteen Japanese SLE patients were studied. SF-36 physical component summary (PCS) and mental component summary (MCS) scores were computed by the US norm-based two-component (US2) and Japanese norm-based three-component (JP3) models, respectively, and compared. Their association with demographics and disease characteristics was also analysed., Results: The US2-PCS scores were significantly higher than the JP3-PCS scores (p < .001); however, the US2-MCS and JP3-MCS scores were not significantly different (p = .16). Bland-Altman analyses demonstrated that the US2-PCS scores were generally higher than the JP3-PCS scores, and their difference was larger in the subjects with lower PCS scores. However, the multiple linear regression analyses for the PCS and MCS scores computed by the different models demonstrated mostly equivalent standardized regression coefficients with the variables., Conclusions: Although the agreement between the US norm-based two-component and Japanese norm-based three-component models of the SF-36 was insufficient, their scores demonstrated similar associations with other variables. The application of the US original version could be acceptable in certain studies depending on the research question., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub-clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline., Methods: The Tasmanian Longitudinal Health Study is a population-based cohort (n = 8583). Biomarkers of systemic inflammation were measured on participants at age 45, and latent profile analysis was used to identify cytokine profiles. Bronchial hyperresponsiveness (BHR) and nitric oxide products in exhaled breath condensate (EBC NOx) were measured at age 50. Participants with spontaneous asthma remission at ages 45 (n = 466) and 50 (n = 318) were re-evaluated at age 53, and associations between baseline inflammatory biomarkers and subsequent asthma relapse and lung function decline were assessed., Results: We identified three cytokine profiles in adults with spontaneous asthma remission: average (34%), Th2-high (42%) and Th2-low (24%). Compared to the average profile, a Th2-high profile was associated with accelerated decline in post-BD FEV 1 /FVC (MD -0.18% predicted per-year; 95% CI -0.33, -0.02), while a Th2-low profile was associated with accelerated decline in both post-BD FEV 1 (-0.41%; -0.75, -0.06) and post-BD FVC (-0.31%; -0.62, 0.01). BHR and high TNF-α during spontaneous remission were associated with an increased risk of asthma relapse. In contrast, we found no evidence of association between EBC NOx and either asthma relapse or lung function decline., Conclusion: BHR and serum inflammatory cytokines have prognostic value in adults with spontaneous asthma remission. At-risk individuals with BHR, Th2-high or Th2-low cytokine profiles may benefit from closer monitoring and on-going follow-up., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up., Methods: We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied., Results: We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P < 0.05 for damage accrual ORs at all time points)., Conclusion: In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications., Methods: We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints., Results: 89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01-2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score., Conclusions: In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE., Competing Interests: Competing interests: SR reports a research grant from Lupus Victoria and postgraduate scholarships from the National Health and Medical Research Council (NHMRC), Arthritis Australia and the Australian Rheumatology Association. YG-J, VG, RK-R and JCS have nothing to disclose. EFM reports grants from Abbvie, Amgen, AstraZeneca, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serano, Genentech, GlaxoSmithKline, Janssen and UCB, as well as consulting fees from AstraZeneca, Biogen, BristolMyersSquibb, Eli Lily, EMD Serano, Novartis, Servier and Zenas, all of which were outside the submitted work. EFM also reports payment or honoraria for educational events from AstraZeneca, Gilead and ONO, meeting support from AstraZeneca, patents with Monash University and AstraZeneca and director role for Rare Voices Australia. AH reports grants from AstraZeneca and Merck Serono outside the submitted work, Sponsorship of the Australian Lupus Registry and Biobank which is chaired by AH is received from Janssen, BMS, AstraZeneca and UCB. AH also reports meeting support from Janssen and consulting fees from Abbvie, Janssen and GSK. AH is honorary treasurer and board member for the Australian Rheumatology Association., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Cognitive dysfunction, and comorbidities such as mood disorder and fibromyalgia, are common in SLE. This study aims to explore the associations between fibromyalgia, mood disorders, cognitive symptoms and cognitive dysfunction in SLE patients, and their impact on quality of life., Methods: We tested cognition in SLE patients and healthy controls, and evaluated cognitive symptoms, mood disorder, fibromyalgia, fatigue and quality of life using patient-reported outcome measures. We examined associations of these comorbidities with both patient-reported cognitive symptoms and cognitive test performance., Results: High fibromyalgia symptom score and history of depression or anxiety were associated with cognitive dysfunction. There were no significant associations between current depression, anxiety symptoms or fatigue score and objective cognitive dysfunction. In contrast, mood disorder symptoms, history of mood disorder, fibromyalgia symptoms and fatigue all had significant associations with patient-reported cognitive symptoms. There were no significant associations between patient-reported cognitive symptoms and objective cognitive dysfunction. Objective cognitive dysfunction, patient-reported cognitive symptoms, history of mood disorder and fibromyalgia symptoms all had significant associations with poorer quality of life; fibromyalgia had the biggest impact., Conclusions: Cognitive symptoms are common in SLE, but there were no associations between cognitive symptoms and objective cognitive dysfunction. Depression, anxiety and fibromyalgia were more consistently associated with patient-reported cognitive symptoms than with objective cognitive dysfunction. These factors all have a significant impact on quality of life. Understanding the discrepancy between patient-reported cognitive symptoms and cognitive test performance is essential to advance care in this area of unmet need., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: The selection and categorisation of laboratory tests in disease activity measures used within systemic lupus erythematosus (SLE) trial endpoints lack strong evidence. We aimed to determine whether longitudinal improvements in routinely measured laboratory tests are associated with measures of clinical improvement in patients with baseline active SLE., Methods: We included patients from a multicentre longitudinal cohort (recruited between May 1, 2013, and Dec 31, 2019) with active SLE (SLEDAI-2K ≥6) coinciding with an abnormality in at least one of 13 routine laboratory tests, at a visit designated as baseline. At 12 months, we analysed associations between thresholds of improvement in individual laboratory test results, measured as continuous variables, and five clinical outcomes using logistic regression. Primary outcomes were damage accrual and lupus low disease activity state (LLDAS), and secondary outcomes were modified SLE responder index (mSRI), physician global assessment (PGA) improvement of at least 0·3, and flare., Findings: We included 1525 patients (1415 [93%] women and 110 [7%] men, 1328 [87%] Asian ethnicity) in separate subsets for each laboratory test. The strongest associations with LLDAS and damage protection were seen with improvements in proteinuria (complete response: adjusted odds ratio [OR] 62·48, 95% CI 18·79-208·31 for LLDAS, OR 0·22, 95% CI 0·10-0·49 for damage accrual), albumin (complete response: adjusted OR 6·46, 95% CI 2·20-18·98 for LLDAS, OR 0·42, 95% CI 0·20-1·22 for damage accrual), haemoglobin (complete response: adjusted OR 1·97, 95% CI 1·09-3·53 for LLDAS, OR 0·33, 95% CI 0·15-0·71 for damage accrual), erythrocyte sedimentation rate (complete response: adjusted OR 1·71, 95% CI 1·10-2·67 for LLDAS, OR 0·53, 95% CI 0·30-0·94 for damage accrual), and platelets (complete response: adjusted OR 4·82, 95% CI 1·54-15·07 for LLDAS, OR 0·49, 95% CI 0·20-1·19 for damage accrual). Improvement in serological tests were mainly associated with PGA and mSRI. White cell and lymphocyte count improvements were least predictive., Interpretation: Improvements in several routine laboratory tests correspond with clinical outcomes in SLE over 12 months. Tests with the strongest associations were discrepant with laboratory tests included in current trial endpoints, and associations were observed across a range of improvement thresholds including incomplete resolution. These findings suggest the need to revise the use of laboratory test results in SLE trial endpoints., Funding: Abbvie., Competing Interests: Declaration of interests KC reports grants from the National Health and Medical Research Council and Royal Australian College of Physicians, personal fees from AstraZeneca, and sponsorship from Janssen and Pfizer. AH reports grants from Merck Serono, AstraZeneca, Janssen, Bristol Myers Squibb and UCB, personal fees from Abbvie, Janssen, and GlaxoSmithKline, sponsorship from Janssen, and honorary treasurer and board participation for Australia Rheumatology Association. SN reports personal fees from Biogen, Boehringer Ingelheim, Janssen, Novartis, Pfizer, and GlaxoSmithKline, sponsorship from Pfizer, and advisory board participation for Biogen. YK reports personal fees from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen, Chugai, Asahi-Kasei, Astellas, and Mitsubishi Tanabe Pharma. MH reports grants from Chugai, and personal fees from GlaxoSmithKline, Chugai, and AstraZeneca. KPLN reports advisory board participation for Abbvie. TT reports grants from Astellas, Asahi-Kasei, Chugai, and Mitsubishe-Tanabe, and personal fees from Astellas and Chugai. YT reports grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, and Boehringer-Ingelheim, and personal fees from Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, and GlaxoSmithKline. MN reports grants from Janssen, and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen and Pfizer. EFM reports grants from Janssen, Astra-Zeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, GlaxoSmithKline, Genentech, UCB, Amgen, Abbvie, and Biogen; personal fees from Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Capella, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Neovacs, Novartis, Sanofi, Servier, UCB, Wolf, and Zenas; sponsorship from AstraZeneca; a patent application with Monash University; and a not-for-profit participation in Rare Voices of Australia. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk., Methods: In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941., Findings: Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0-5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31-0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29-0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12-0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02-0·96]; p=0·046)., Interpretation: LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used., Funding: The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study., Competing Interests: Declaration of interests SVN has received consulting fees from Biogen and Boehringer Ingelheim; lecture or speaker fees from Janssen, Novartis, Pfizer, and GlaxoSmithKline; conference registration fees from Pfizer; and payment from Biogen for participation on an advisory board. YK has received payment or honouria from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MH has received payment for post-marketing surveillance from GlaxoSmithKline; research grants from Novartis Pharma; and honoraria for lectures for GlaxoSmithKline, AstraZeneca, and Astellas Pharma. TT has received grants from Astellas, Asahi Kasei, Chugai, and Mitsubishi Tanabe; and consulting fees from Astellas and Chugai. KPLN has received advisory board participation fees from AbbVie. DYY is an employee of Janssen. CSK is a stock owner and an employee of Janssen. MN has received research grants from Janssen; and consulting fees from AstraZeneca, Boehringer & Ingelheim, GlaxoSmithKline, and Janssen. EFM has received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genetech, Janssen, Novartis, Servier, and EMD Serono. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort., Methods: Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity., Results: Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS., Conclusion: Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments., (© 2021 American College of Rheumatology.)

Objective: Randomized controlled trials (RCTs) in SLE (lupus) typically adopt composite responder definitions as primary efficacy endpoints; however, outcomes within individual organ domains are also important to understand. The aim of this scoping review was to evaluate how organ-specific disease activity and therapeutic responses have been measured and reported in lupus RCTs., Methods: We searched MEDLINE, EMBASE, Cochrane registry and clinicaltrials.gov. Eligible studies were RCTs investigating efficacy of an immune-directed drug therapy in active SLE, published January 2000-March 2021, excluding studies limited to lupus nephritis. Data were extracted independently in duplicate into a template and summarized descriptively., Results: Thirty-four RCTs were included, of which 32 (94%) reported activity and/or responses in at least one organ domain. Study populations had a high, although variable, frequency of baseline musculoskeletal and mucocutaneous activity and low, but also variable, representation of other domains. Definitions of organ-specific responses were inconsistent, even within individual instruments. Response in most organ domains were evaluated using BILAG and SLEDAI components but meaningful comparison between treatment arms was limited by small subgroups analysed in a post hoc fashion. Specific mucocutaneous and arthritis instruments were also used, including within pre-specified organ-specific endpoints, which discriminated between treatment arms in some studies., Conclusion: Mucocutaneous and musculoskeletal manifestations predominate in SLE RCTs. Organ-specific outcome measures are commonly reported, but definitions of involvement and response are inconsistent. Research into the development of new outcome measures for key organ domains, and validation and comparison of response definitions using existing instruments, is needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes., Methods: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI)., Results: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients., Conclusion: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality., (© 2022. The Author(s).)

Objectives: Type 1 interferon (IFN) is key to the pathogenesis of SLE, evidenced by the expression of IFN-stimulated genes (ISGs) in most patients, but the clinical utility of serial ISG assessment remains unknown. With the emergence of IFN-blocking drugs, we aimed to examine IFN status in relation to clinical findings longitudinally to provide insights into the value of testing ISG levels over time., Methods: Clinical data and whole blood were collected prospectively on adult patients with SLE from a single tertiary lupus centre. IFN status was measured using a panel of ISGs., Findings: 729 samples were analysed from 205 patients. At baseline, 62.9% of patients were IFN high, 30.2% IFN low and 6.8% borderline. 142 patients had multiple samples collected, and 87.3% of these demonstrated stable ISG status over time. In longitudinal follow-up, IFN high patients had higher activity in multiple organ domains and spent less time in Lupus Low Disease Activity State, but IFN score did not correlate with SLE Disease Activity Index in individual patients. In the small subset of patients who had large fluctuations in ISG across the observation period, most had high-dose glucocorticoids that correlated with ISG suppression. However, low-moderate-dose glucocorticoids did not suppress ISG expression., Conclusion: Although IFN high status is associated with indicators of more severe SLE, in the majority of patients, ISGs are stable across time and do not correlate with disease activity. Changes in ISG expression may be seen with high-dose, but not routine dose, glucocorticoid exposure. These findings suggest baseline but not serial ISG measurement may be of value in the management of SLE., Competing Interests: Competing interests: Outside the scope of this work, EM has received consulting fees from AbbVie, AstraZeneca, Amgen, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genetech, Janssen, Servier and UCB, and research grants from AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono and Janssen. AH has received research grants from AstraZeneca, Merck and BMS., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)